My laboratory recently uncovered an unexpected and intriguing role for a specific population of monocyte-derived cells during skin wound healing. In particular, we identified that CD301b+ cells, which is expressed by a subset of monocyte-derived cells including dendritic cells and macrophages, are essential for skin wound healing including regeneration of dermal adipocytes. Our findings are important for several reasons. First, heterogeneity and plasticity with populations of monocyte-derived cells have been recently discovered and which cell type is essential for promoting skin wound healing is not known. Second, our data reveal an essential role for a subclass of monocyte-derived cells that express CD301b in skin wound repair. Finally, monocytes and their derivatives are a tractable cell type to create a personalized therapy to promote healing in patients with chronic wounds. Through three focused and complementary Specific Aims, the work proposed in this application will take advantage of multiple genetic mouse models that allow specific depletion of monocyte derivatives, transplantation assays, cell culture models, and a novel bioanalytical assay platform to identify the secretome of individual monocytes isolated from the skin. We will (1) identify the role of specific populations of monocyte- derived cells during skin wound healing, (2) analyze the function of the secretome of monocyte-derived cells in controling dermal wound healing, and (3) define whether specific monocyte-derived cell populations function in defective wounds of aged and diabetic mice. These studies will identify specific pro-healing cell populations that can be utilized to promote healing in human patients with defective wound healing or other skin disorders.